This proposal investigates the mechanism(s) underlying the interactions between adiposity-related hormones, insulin and leptin, and nutrient-related signals in the control of key neuronal subsets in the hypothalamic arcuate nucleus (ARC), and seeks to clarify how these interactions influence the perception of satiety. Both insulin and leptin are hypothesized to act upon ARC neurons to reduce food intake via activation of cellular responses involving the insulin receptor substrate (IRS)-phosphatidylinositol 3-OH kinase (PI3K) pathways. One mechanism whereby leptin and insulin are hypothesized to reduce food intake is by potentiating the response to endogenous signals generated in response to food ingestion, including cholecystokinin (CCK), that hasten the onset of satiety. Specifically, we hypothesize that a descending projection from the hypothalamus links responses elicited by adiposity-related signals to hindbrain circuits that respond to satiety signals. Via this mechanism, a sustained reduction of body fat stores (which lowers plasma insulin and leptin levels) is proposed to attenuate the response to satiety signals and thereby increase meal size. Specific Aim 1 investigates whether the ability of insulin or leptin to potentiate the response to CCK is dependent on hypothalamic PI3K signaling. An exciting new area of study revolves around the hypothesis that acute neuronal effects of insulin and leptin converge on those induced by intracellular long chain fatty acyl CoA (LCFACoA) molecules. Specific Aims 2-4 will expand upon our preliminary data demonstrating that LCFACoA content is regulated by changes of energy balance and by adiposity-related hormones, and will clarify the mechanisms underlying these effects. Specific Aim 5 investigates whether accumulation of LCFACoA in the ARC mimics the effect of leptin to potentiate the response to satiety signals. Together, these aims have the potential to fundamentally revise our understanding of signaling networks controlling energy homeostasis and obesity pathogenesis, and will thereby provide much needed new direction for ongoing efforts to develop more successful approaches to obesity treatment.